Presentation

In most cases, adrenal insufficiency manifests before dysfunction of other endocrine glands cause clinical symptoms. Consequently, patients presenting with SS often show unspecific symptoms corresponding to Addison's disease upon the first presentation. They usually claim fatigue, weakness, nausea, vomiting, diarrhea, constipation and abdominal pain. Patients tend to lose their appetite and weight, but they may report cravings for salt. Hypotension is often registered. During the physical examination of skin and mucous membranes, hyperpigmented areas of may be recognized, particularly in skin folds and oral cavity. On the other hand, vitiligo may be noted. Vitiligo is considered a comorbidity and a possible marker of autoimmune processes, not a consequence of Addison's disease.

Additional findings may point at the involvement of other organs. Further diagnostic measures don't differ from those applied to determine single endocrinopathies and should be taken if the results of blood sample analyses imply a certain entity. An ACTH stimulation test is recommended to confirm primary adrenal insufficiency. Thyroid function tests, for instance, are indicated if the clinical presentation and serum levels of T3, T4, and TSH suggest hypothyroidism or Graves disease.

Measurement of organ-specific autoantibodies is a sensitive method that allows for an early detection of endocrinopathies before tissue damage suffices to cause symptoms [10].

Patients diagnosed with SS (and possibly even those only suffering from Addison's disease) should undergo regular follow-ups in order to identify comorbidities before severe symptoms manifest. Such follow-ups should comprise blood sample analyses and thyroid function tests.

Treatment

Treatment regimes correspond to those described for the individual endocrinopathies that form part of SS. Before initiation of treatment, a complete workup needs to be performed. Patients suffering from multiple endocrinopathies may present with adverse events to otherwise well-tolerated drugs. Substitution of thyroid hormones, for instance, may trigger an Addisonian crisis in people suffering from concurrent adrenal insufficiency.

The following drugs are the mainstays of SS therapy:

So as to compensate for adrenal insufficiency, patients receive hydrocortisone and fludrocortisone to replace glucocorticoids and mineralocorticoids.

Prognosis

There is no causative treatment for SS; components of this syndrome have to be treated individually and symptomatically. In general, hormone deficits can be compensated for by means of drug therapy and patients are able to lead a relatively normal life. However, Addisonian crisis, thyrotoxic crisis, and diabetic ketoacidosis are life-threatening complications of decompensated endocrinopathies and it is of utmost importance that patients are aware of those risks. Additionally, significant morbidity may arise from long-term decompensation of serum hormone levels, e.g., peripheral neuropathy, nephropathy, and retinopathy in the case of hyperglycemia due to diabetes mellitus type 1.

Etiology

SS is an autoimmune disorder presumably caused by determined gene patterns. Rather than being triggered by a single mutation, polygenic inheritance seems to lead to this polyendocrinopathy. Consequently, precise inheritance patterns cannot be defined; some genes that contribute to a predisposition for SS may be inherited as an autosomal dominant trait, others in an autosomal recessive manner. Sex chromosomes don't seem to be involved in SS inheritance.

It has been suggested that certain HLA haplotypes may predispose for SS. This hypothesis originates from studies conducted with patients suffering from Addison's disease, a main component of SS. Here, haplotypes comprising HLA-DR3, HLA-DR4, HLA-DQ2, and HLA-DQ8 are associated with a high risk for adrenal insufficiency [3]. Further research is required to confirm that these findings are also applicable to SS.

Of note, SS may also be diagnosed in patients whose family has no medical history of autoimmune disorders. It is not yet clear whether these sporadic cases correspond to recombination, de novo mutation or diseases triggered by environmental factors in a given genetic background.

Epidemiology

In developed countries, the overall incidence of SS has been estimated to be less than 5 per 100,000 inhabitants [5]. The risk of developing SS may be increased 50-fold in people who inherited one of the aforementioned HLA haplotypes and is highest in those patients previously diagnosed with Addison's disease. These estimates are based on the following observations:

The overall incidence of Addison's disease is 10 per 100,000 inhabitants and 500 per 100,000 carriers of determined HLA haplotypes [3].

People suffering from an autoimmune disease are more prone to develop another, similar disorder than their healthy peers [6]. In the case of Addison's disease, up to 50% of affected individuals will develop another autoimmune disorder, e.g., thyroid disorders or diabetes mellitus [7].

With regards to SS, women are affected about three times as often as men. Symptom onset typically occurs during the third or fourth decade of life, but this type of polyendocrinopathy has also been diagnosed in pediatric and elder patients [5].

Sex distribution

Age distribution

Pathophysiology

The pathogenesis of SS is poorly understood and only general statements can be made regarding the pathophysiological events leading to dysfunction of multiple endocrine glands and other organs in this pathology.

As has been indicated above, SS is primarily considered a genetic disorder. With regards to HLA haplotypes and polymorphisms related to SS, penetrance and expressivity seem to vary widely. Symptom onset rarely occurs in childhood and the patient's immune system works just fine until well into adulthood. Thus, environmental, dietary or intrinsic factors are assumed to trigger an autoimmune response in patients predisposed to this type of polyendocrinopathy. In this context, SS may likely be classified as a multifactorial disease.

The nature of SS trigger(s) is not clear; they induce an autoimmune response and production of distinct, organ-specific autoantibodies. Their target structures, namely adrenal glands, thyroid cells and the endocrine pancreas, are progressively destroyed by the patient's own immune system. Symptom onset does not occur until considerable shares of hormone-producing cells are destructed.

SS is considered a genetic disorder, but the disease has not been related to determined polymorphisms or mutations. According to current knowledge, polygenic inheritance and environmental factors contribute to predisposition and symptom onset. First symptoms typically manifest in adulthood, but patients pertaining to all age groups may be affected. Women are affected significantly more often than men.

Patient Information

SS is a genetic disorder, i.e., inheritance of certain genomic pattern predisposes patients for this disease. However, penetrance and expressivity vary largely and neither do all patients that carry those patterns develop SS nor do all SS patients present the same symptoms.

Symptom onset usually occurs in adulthood and is caused by the induction of an autoimmune response. Here, the body's immune system produces antibodies against its adrenal and thyroid glands, against the pancreas that secretes insulin and sometimes also against other endocrine glands.

Clinical examination and laboratory analyses of blood samples allow for a tentative diagnosis of polyendocrinopathy. Special tests have to be carried out to confirm adrenal insufficiency, thyroid malfunction or diabetes mellitus, though.

Measurement of autoantibodies is required to proof that observed symptoms are provoked by an autoimmune response.

Treatment

Treatment mainly consists in the substitution of lacking hormones. Lifelong therapy is required.

Glucocorticoids and mineralocorticoids are prescribed in case of Addison's disease; levothyroxine is required if SS patients suffer from hypothyroidism. In the case of Graves disease - a form of hyperthyroidism - excess production of thyroid hormones needs to be limited by means of medication, radiolabeled iodine or surgery. Diabetes mellitus type 1 is treated with insulin.

Compliance with drug therapy significantly affects the patient's prognosis since decompensation of hormonal levels may cause the Addisonian crisis, thyrotoxic crisis or diabetic ketoacidosis, which are life-threatening events.

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